TY - JOUR
T1 - Cryo-EM reveals the conformational epitope of human monoclonal antibody PAM1.4 broadly reacting with polymorphic malarial protein VAR2CSA
AU - Raghavan, Sai Sundar Rajan
AU - Dagil, Robert
AU - Lopez-Perez, Mary
AU - Conrad, Julian
AU - Bassi, Maria Rosaria
AU - Quintana, Maria Del Pilar
AU - Choudhary, Swati
AU - Gustavsson, Tobias
AU - Wang, Yong
AU - Gourdon, Pontus
AU - Ofori, Michael Fokuo
AU - Christensen, Sebastian Boje
AU - Minja, Daniel Thomas Remias
AU - Schmiegelow, Christentze
AU - Nielsen, Morten Agertoug
AU - Barfod, Lea
AU - Hviid, Lars
AU - Salanti, Ali
AU - Lavstsen, Thomas
AU - Wang, Kaituo
N1 - Copyright: © 2022 Raghavan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2022
Y1 - 2022
N2 - Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria.
AB - Malaria during pregnancy is a major global health problem caused by infection with Plasmodium falciparum parasites. Severe effects arise from the accumulation of infected erythrocytes in the placenta. Here, erythrocytes infected by late blood-stage parasites adhere to placental chondroitin sulphate A (CS) via VAR2CSA-type P. falciparum erythrocyte membrane protein 1 (PfEMP1) adhesion proteins. Immunity to placental malaria is acquired through exposure and mediated through antibodies to VAR2CSA. Through evolution, the VAR2CSA proteins have diversified in sequence to escape immune recognition but retained their overall macromolecular structure to maintain CS binding affinity. This structural conservation may also have allowed development of broadly reactive antibodies to VAR2CSA in immune women. Here we show the negative stain and cryo-EM structure of the only known broadly reactive human monoclonal antibody, PAM1.4, in complex with VAR2CSA. The data shows how PAM1.4's broad VAR2CSA reactivity is achieved through interactions with multiple conserved residues of different sub-domains forming conformational epitope distant from the CS binding site on the VAR2CSA core structure. Thus, while PAM1.4 may represent a class of antibodies mediating placental malaria immunity by inducing phagocytosis or NK cell-mediated cytotoxicity, it is likely that broadly CS binding-inhibitory antibodies target other epitopes at the CS binding site. Insights on both types of broadly reactive monoclonal antibodies may aid the development of a vaccine against placental malaria.
KW - Humans
KW - Female
KW - Pregnancy
KW - Antigens, Protozoan
KW - Malaria, Falciparum/parasitology
KW - Epitopes
KW - Antibodies, Protozoan
KW - Antibodies, Monoclonal
KW - Cryoelectron Microscopy
KW - Placenta/metabolism
KW - Plasmodium falciparum/metabolism
KW - Erythrocytes/parasitology
KW - Malaria
KW - Chondroitin Sulfates/metabolism
U2 - 10.1371/journal.ppat.1010924
DO - 10.1371/journal.ppat.1010924
M3 - Journal article
C2 - 36383559
VL - 18
JO - P L o S Pathogens (Online)
JF - P L o S Pathogens (Online)
SN - 1553-7374
IS - 11
M1 - e1010924
ER -